We propose using Positron Emission Tomography (PET) based molecular imaging of key molecules and biochemical pathways implicated in the abnormal proliferation and treatment failure of castrate resistant metastatic prostate cancer, the lethal variant of the disease. Studies planned are interdisciplinary and translational: collaboration for basic studies is with Dr.s N. Rosen/D. Solit (Molecular Oncogenesis Lab.) and for clinical studies with Dr.s H. Scher/M. Morris (GU Oncology). This project is a continuation of project 4 in the MSKCC ICMIC P50 CA86438. In this competitive renewal, we will refine the androgen receptor (AR), her2 receptor (her2) and heat shock protein 90 (HSP90) imaging methods that were previously invented or developed under ICMIC. Our focus on these molecular imaging methods is based on the biologic links between these 3 molecules including the key role of AR in castrate-resistant prostate cancer and the clinical potential of her2, HSP90 and histone deacetylase (HDAC) inhibitor drugs for therapy of prostate and other major cancers. In specific aim 1A, we will develop a kinetic-method for quantification of AR using [18F] 16B dihydrotestosterone (FDHT) in castrate resistant prostate cancer, with the rationale that this will improve treatment selection and monitoring for drugs which target AR. Based on our prior findings, in specific aim 1B, we propose a medicinal chemistry path to improve AR radioligands, through addition of appropriate side chains, to retard metabolite formation and increase AR binding affinity. In specific aim 2, we continue development of her2 targeting based on PET labeled antibody forms of herceptin IgG, fab'2, and fab'. In specific aim 3, we will explore the potential of lodine-124 labeled purine based HSP90 inhibitors as imaging agents for HSP90. In specific aim 4, we will continue to optimize clinical imaging paradigms of the pharmacodynamic effects of therapies for castrate resistant prostate cancer, using FDHT, FDG, C-11 methionine, and F-18 L-Thymidine (FLT). Clinical protocols are planned in prostate cancer for drugs which are known to inhibit AR, HSP90 and her2 molecules, such as the AR targeting agents, ansamycin and purine based HSP90 inhibitors, herceptin and the HDAC inhibitors. In summary, building on our prior research, we plan to continue the process of discovery, development and translation of molecular imaging methods into advanced practice leading to improved diagnosis and therapy in human prostate cancer.